Epothilone derivatives, a method for the production thereof, and their use

ABSTRACT

The present invention relates to epothilon derivatives, processes for their production and their use in the manufacture of medicaments and plant protection agents.

This application is a 371 of PCT/EP99/03159 filed May 7, 1999, nowWO99/58534 Nov. 18, 1999.

The present invention relates generally to epothilon derivatives, toprocesses for their production and to their use in the manufacture ofmedicaments and plant protection agents. The invention relatesespecially to epothilon derivatives of the general formulae 2 to 6 shownbelow and to their use as medicaments and plant protection agents.

In the above formulae:

-   R¹=a H atom or a C₁- to C₈-alkyl group, preferably a C₁- to C₆-alkyl    group, especially preferably a C₁- to C₄-alkyl group, especially a    methyl, ethyl, propyl or butyl group,-   R²=a monocyclic aromatic group, such as a 5- or 6-membered aromatic    group (such as a phenyl ring) or a vinyl group, each of which may be    substituted in the ortho- and/or meta- and/or para-position(s) by    one, two, three, four or five, especially one or two, halogen atoms    and/or OR⁴ and/or NR⁵R⁶ groups and/or alkyl and/or alkenyl and/or    alkynyl groups, wherein R⁴, R⁵ and R⁶ each independently of the    others have the same meanings as R¹, but are independent of R¹, or-   R²=a monocyclic 5- or 6-membered heteroaromatic group which may have    one or more, especially one or two, O and/or N and/or S atoms in the    ring and/or may have OR⁴ and/or NR⁵R⁶ groups and/or alkyl and/or    alkenyl and/or alkynyl groups as substituents, wherein R⁴, R⁵ and R⁶    are as defined above. In the definition of R² there are especially    preferred C₁–C₆-alkyl or C₂–C₆-alkenyl and -alkynyl groups,    especially C₁–C₄-alkyl or C₂–C₄-alkenyl and -alkynyl groups. As    alkyl groups there are especially preferred methyl, ethyl, propyl    and butyl groups and as heteroaromatic groups 6-membered    heteroaromatic groups,-   Hal=a halogen atom, such as Br or I,-   X—Y=a group of the formula —CH₂CH—OP or —CH═CH—, and-   P=a protecting group, such as TMS.

The compounds according to the invention may be produced as follows:

Compounds of the formula (2) may be produced by reacting compounds ofthe formula (1)

as described in DE 195 42 986, the radicals being as defined above. Inthat reaction, especially the following conditions (i), (iii) andoptionally (after (i)) also (ii) may be used:

-   (i)    -   (a) O₃ in a solvent, such as CH₂Cl₂, and    -   (b) reductive working-up, for example with Me₂S;-   (ii)    -   (a) (CH₃CO)₂O, HCO₂H, NEt₃, DMAP;    -   (b) DBU; and    -   (c) MeOH, NH₃; and-   (iii) Me₃SiCl, NEt₃.

Compounds of the formula (3) are obtainable by reacting a compound ofthe formula (2) with a compound of the formula HC[B(OR)₂]₃, such astris(ethylenedioxyboryl)methane; R may be an alkyl or alkenyl group asdefined above.

In the reaction there is optionally used a strong base, such as aC₁–C₄-alkyl-Li compound (such as butyllithium) or adi-C₁–C₄-alkylamine-Li compound (such as a dimethylamine-lithiumcompound). The reaction is generally carried out at low temperatures,such as, for example, at temperatures of less than −30° C., preferablyat temperatures of less than −50° C., especially preferably attemperatures of at least −78° C. Further reaction conditions may befound in D. Schummer, G. Höfle in Tetrahedron 1995, 51, 11219.

For example, a compound of the formula (2) is reacted withtris(ethylenedioxyboryl)methane and butyllithium at −78° C. to form acompound of the formula (3).

A compound of the formula (4) may be produced from a compound of theformula (3) by reaction with N-iodo- or N-bromo-succinimide, optionallyin a polar solvent, such as acetonitrile. Further reaction conditionsmay be found in the following literature reference: N. A. Petasis, I. A.Zavialor, Tetrahedron Lett. 1996, 37, 567.

For the production of a compound of the formula (5), a compound of theformula (3) may be reacted within the framework of a Suzuki couplingwith a compound of the formula R²—Z, wherein R² has the meanings givenabove and Z may be a halogen atom or a group of the formula —OSO₂CF₃,—CH═CHI, —CH═CHOSO₂CF₃. The group R²—Z may especially have the followingstructures:

wherein A¹ represents O, S, N or C atoms and the substituents O—, N— andC— correspond to the above-described groups OR⁴, NR⁵R⁶ and alkyl,alkenyl and/or alkynyl groups.

Especially preferred as substituents “C” are C₁–C₆-alkyl orC₂–C₆-alkenyl and/or -alkynyl groups, especially C₁–C₄-alkyl orC₂–C₄-alkenyl and/or -alkynyl groups. As alkyl groups there areespecially preferred methyl, ethyl, propyl and butyl groups.

Alternatively, a compound of the formula (5) may be produced by reactinga compound of the formula (4) by means of a Stille coupling with R²—SnR³₃, wherein R² is as defined above and R³ is a C₁- to C₆-alkyl group,preferably a C₁- to C₄-alkyl group and especially preferably a methyl,ethyl, propyl or butyl group. In addition, the compound R²—SnR³ ₃ mayhave one of the following structures:

wherein the radicals and substituents are as defined above.

Furthermore, according to the invention, a compound of the formula (6)may be produced by removing the protecting group from the compound ofthe formula (5), for example with a weak acid, such as citric acid, orcompounds such as TBAF, pyridine×HF. Optionally an alcohol, such asmethanol, may be used as solvent, the temperature preferably beingadjusted to values of, for example, from 40 to 60° C., preferably about50° C.

In summary, the compound of the formula (6) may be produced by theabove-described steps (epothilon A or B→(2)→(3)→(4)→(5)→(6) or epothilonA or B →(2)→(3)→(5)→(6)).

According to the invention there are also disclosed medicaments thatcontain at least one of the compounds (2), (3), (4), (5) or (6) andoptionally customary carriers, diluents and adjuvants.

Such compounds may especially be used also as cytostatic agents and forplant protection in agriculture and/or forestry and/or in horticulture,the compounds optionally being used together with one or more customarycarriers, adjuvants and/or diluents.

EXAMPLES

Synthesis of the Ketone Derivatives 2

For a detailed description see DE 195 42 986 A1.

Synthesis of the Alkenylboronic Acid Derivatives 3

(see also D. Schummer, G. Höfle, Tetrahedron 1995, 51, 11219)

Typical Example (R¹═H, X—Y═CH₂CHOTMS):

A solution of tris(ethylenedioxyboryl)methane (0.30 g, 1.5 mmol) inCH₂Cl₂/THF (1:1; 4 ml) was prepared and cooled under inert gas to −78°C. At that temperature, butyllithium (1.6M solution in hexane; 0.73 ml,1.2 mmol) was added dropwise wise in the course of 10 minutes. After 2hours, ketone 2 (81 mg, 0.15 mmol) in CH₂Cl₂/THF (1:1, 2 ml) was added,heated to room temperature and stirred for 17 hours. After the additionof MeOH (2 ml), the clear reaction solution was purified by means ofpreparative HPLC (Lichroprep RP-18, CH₃CN/H₂O 75:25). 57 mg (65%) ofalkenylboronic acid 3 were obtained in the form of an E/Z-isomericmixture (6:4).

Selected typical data: LC-MS (ESI-MS): 585 (M⁺+H); ¹H-NMR: (300 MHz,CD₃OD): E-isomer: 1.91 (S, 3H), 5.16 (d, 1H, 10 Hz), 5.49 (s, 1H),Z-isomer; 1.85 (d, 3H, 1.1 Hz), 4.93 (s, 1H), 5.26 (d, 1H, 9.6 Hz).

Synthesis of the Iodovinyl Derivatives 4

(see also N. A. Petasis, I. A. Zavialor, Tetrahedron Lett. 1996, 37,567)

Typical Example (R¹═H, X—Y═CH₂CHOTMS):

At room temperature, N-iodosuccinimide (6.0 mg, 27 μmol) was added underinert gas and with the exclusion of light to a solution ofalkenylboronic acid 3 (12 mg, 21 μmol; E/Z 9:1) in CH₃CN (150 μl) andstirred for 3 hours. After concentration, the residue was purified bymeans of preparative thin-layer chromatography (SiO₂, CH₂Cl₂/MeOH 95:5).9 mg (66%) of the iodovinyl derivative 4 were isolated in the form of anE/Z-isomeric mixture (9:1).

Selected typical data: LC-MS (ESI-MS): 667 (M⁺+H); ¹H-NMR: (300 MHz,CDCl₃); E-isomer: 1.82 (d, 3H, 1.1 Hz), 5.36 (d, 1H, 11 Hz), 6.43 (s,1H), Z-isomer: 1.84 (d, 3H, 1.1 Hz), 5.54 (d, 1H, 10.5 Hz), 6.09 (s,1H).

Suzuki Coupling of the Alkenylboronic Acid 3

(see also A. Suzuki, Acc. Chem. Res. 1982, 15, 178; A. Torrado, S.Lopez, R. Alvarez, A. R. De Lera Synthesis, 1995, 285)

Typical Example (R¹=H, X—Y═CH₂CHOTMS, R²=Ph):

A solution of alkenylboronic acid 3 (12 mg, 21 μmol; E/Z 2:8) andthallium ethanolate (2M solution in EtOH; 12 μl, 24 μmol) in THF (150μl) was stirred at room temperature for 15 minutes, then a solution ofphenyl iodide (4.0 μl, 6.0 mg, 29 μmol) andtetrakis(triphenylphosphino)-palladium (7.1 mg, 6.2 μmol) in THF (150μl) was added dropwise in 30 minutes and again stirred for 30 minutes.After purification by means of preparative thin-layer chromatography(SiO₂, CH₂Cl₂/Et₂O 95:5) the phenyl-analogous epothilon 5 (10 mg, 79%,E/Z 2:8) was obtained in the form of a colourless solid.

Selected typical data: LC-MS (ESI-MS): 617 (M⁺+H); ¹H-NMR: (300 MHz,CDCl₃): E-isomer: 1.87 (d, 3H, 1.4 Hz), 5.35 (d, 1H, 10.7 Hz), 6.54 (s,1H), Z-isomer: 1.80 (d, 3H, 1.5 Hz), 5.61 (d, 1H, 10.2 Hz), 6.41 (s,1H).

Stille Coupling of the Iodovinyl Derivatives 4

(see also K. C. Nicolaou, Y. He, F. Roschangar, N. P. King, D.Vourloumis, T. Li Angew. Chem. 1998, 110, (1/2), 89).

1. A compound of the formula:

wherein R¹ is a H atom or a C₁- to C₈-alkyl group, X—Y is a group of theformula —CH₂CH(OP)— or —CH═CH—, and P is a protecting group.
 2. Acompound of the formula:

wherein the radicals are as defined in claim
 1. 3. A compound offormula:

wherein the residues R¹, X—Y and P are defined as in claim 1, and Hal isa halogen.
 4. A compound of the formula:

wherein the residue R¹ is a hydrogen atom or a C₁₋₈-alkyl group, and Pis a protective group and X—Y is a group of formula —CH₂CH(OP)— orCH═CH, and R² is a monocyclic aromatic which can be substituted by ahalogen atoms and/or OR⁴- and/or NR⁵R⁶- and/or alkyl, alkenyl and/oralkynyl groups in ortho- and/or meta- and/or para-position, or amonocyclic 5- or 6-membered hetero aromatic, which can be optionallysubstituted with one or several O- and/or N- and/or S-atoms in the ringand/or which can be optionally substituted with OR⁴- and/or NR⁵R⁶-and/or alkyl, alkenyl and/or alkynyl groups as substituents, wherein theresidues R⁴, R⁵ and R⁶ are each independently a hydrogen atom or aC₁₋₈-alkyl group, wherein (i) XY is excluded as group of formula —CH═CH—if R¹ is a hydrogen atom or a C₁₋₄-alkyl group and R² is a monocyclichetero aromatic having a N atom or a N and a S atom in its ring and aC₁-alkyl substituent and (ii) XY is excluded as group of formula —CH₂CH(OP)— if R¹ is a hydrogen atom or a C₁₋₄-alkyl group and R² is amonocyclic hetero aromatic having a N atom or a N and a S atom in itsring and a C₁-alkyl substituent.
 5. A compound of the formula:

wherein the residues are as defined in claim 4 and, if X—Y means a groupof formula —CH₂CH—OP, the protective group P has been removed, wherein(i) XY is excluded as group of formula —CH═CH— if R¹ is a hydrogen atomor a C₁₋₄-alkyl group and R² is a monocyclic hetero aromatic having a Natom and a S atom in its ring and a C₁-alkyl substituent and (ii) XY isexcluded as group of formula —CH₂CH(OP)— if R¹ is a hydrogen atom or aC₁₋₄-alkyl group and R² is a monocyclic hetero aromatic having a N atomor a N atom and a S atom or a N atom and a O atom in its ring and aC₁-alkyl substituent.
 6. A compound of formula:

wherein the residues are defined as in claim 4 and, if X—Y means a groupof formula —CH₂CH(OP)—, the protective group P has been removed, wherein(i) XY is excluded as group of formula —CH═CH— if R¹ is a hydrogen atomor a C₁₋₄-alkyl group and R² is a monocyclic hetero aromatic having a Natom and/or a S atom in its ring and a C₁-alkyl substituent and (ii) XYis excluded as group of formula —CH₂CH(OP)— if R¹ is a hydrogen atom ora C₁₋₄-alkyl group and R² is a monocyclic hetero aromatic having a Natom or a N atom and a S atom or a N atom and an O atom in its ring anda C₁-alkyl substituent.
 7. A compound as in claims 1, 2, 3, 4, 5 or 6wherein R¹, R⁴, R⁵ and R⁶ are a hydrogen atom or a C₁₋₆-alkyl group. 8.A compound as in claims 4, 5, 7 or 6 wherein the substituents of themonocyclic aromatic and/or hetero aromatic are C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, fluorine, chlorine, bromine or iodine.
 9. A compound as inclaims 4, 5, 7, 8 or 6 wherein the monocyclic aromatic and/or monocyclichetero aromatic is optionally substituted with 1, 2 or 3 substituentsand the hetero aromatic is optionally substituted with 1, 2 or morehetero atoms in the ring.
 10. Process for the preparation of a compoundof the formula:

wherein R¹ is a H atom or a C₁- to C₈-alkyl group, X—Y is a group of theformula —CH₂CH(OP)— or —CH═CH—, and P is a protecting group, comprisingreacting a compound of the formula:

wherein R¹ is a H atom or a C₁- to C₈-alkyl group X—Y is a group of theformula —CH₂CH(OP)— or —CH═CH—, and P is a protecting group, with acompound of the formula HC[B(OR)₂]₃, wherein R is a H atom or a C₁- toC₈-alkyl group.
 11. Process for the preparation of a compound of theformula:

wherein R¹ is a H atom or a C₁- to C₈-alkyl group, X—Y is a group of theformula —CH₂CH(OP)— or —CH═CH—, P is a protecting group, and Hal is ahalogen, comprising reacting a compound of the formula:

wherein R¹ is a H atom or a C₁- to C₈-alkyl group, X—Y is a group of theformula —CH₂CH(OP)— or —CH═CH—, and P is a protecting group, with N-iodoor N-bromo-succinimide.
 12. Process for the preparation of a compound offormula:

wherein a compound according to claim 2 is reacted by a Suzuki couplingwith a compound of formula R²—Z, wherein R² is a monocyclic aromaticwhich can be substituted by halogen atoms and/or OR⁴- and/or NR⁵R⁶-and/or alkyl, alkenyl and/or alkynyl groups in ortho and/or meta- and/orpara-position, or a monocyclic 5- or 6-membered hetero aromatic, whichcan be optionally substituted with one or several O- and/or N- and/orS-atoms in the ring and/or which can be optionally substituted with OR⁴-and/or NR⁵R⁶- and/or alkyl, alkenyl and/or alkynyl groups assubstituents and Z can be a halogen atom or a group of formula —OSO₂CF₃,—CH═CHI, —CH═CHOSO₂CF₃.
 13. Process for the preparation of a compound offormula:

wherein a compound according to claim 3 is reacted by a silent coupling(stille Kupplung) with R₂—SNR³ ₃, wherein R² is a monocyclic aromaticwhich can be substituted by halogen atoms and/or OR⁴- and/or NR⁵R⁶-and/or alkyl, alkenyl and/or alkynyl groups in ortho- and/or meta-and/or para-position, or a monocyclic 5- or 6-membered hetero aromatic,which can be optionally substituted with one or several O- and/or N-and/or S-atoms in the ring and/or which can be optionally substitutedwith OR⁴- and/or NR⁵R⁶- and/or alkyl, alkenyl and/or alkynyl groups assubstituents and R³ is a C₁₋₆-alkyl group.
 14. Process for thepreparation of a compound of formula:

wherein the protective group is removed from a compound according toclaim
 4. 15. Process for the preparation of a compound of formula:

wherein it comprises the process steps as disclosed in claims 10, 11,12, 13 or
 14. 16. A pharmaceutical composition comprising at least oneof the compounds described in claims 1, 2, 3, 4, 5, 7, 8, 9 or 6 andoptionally carriers, diluents and/or auxiliary agents.
 17. Thepharmaceutical composition according to claim 16, wherein said compoundis cytostaticum.
 18. A method of protecting plants in agriculture and/orforest culture and/or horticulture, comprising administering atherapeutically effective amount of at least one compound described inclaim 1 and optionally carriers, diluents and/or auxiliary agents.
 19. Acompound according to claim 6, wherein the substituents of themonocyclic aromatic and/or hetero aromatic are a C₁₋₆-alkyl,C₂₋₆-alkenyl or C₂₋₆-alkynyl group or a halogen atom.
 20. A compoundaccording to claim 6, wherein the monocyclic aromatic and/or monocyclichetero aromatic is optionally substituted with 1, 2 or 3 substituentsand the hetero aromatic is optionally substituted with 1, 2 or morehetero atoms in the ring.
 21. A compound according to claim 19, whereinthe substituents of the monocyclic aromatic and/or hetero aromatic areC₁₋₄-alkyl, C₂₋₄-alkenyl or C₂₋₄-alkynyl groups.